Structural Modification Endows Small-Molecular SN38 Derivatives with Multifaceted Functions

Abstract

As a camptothecin derivative, 7-ethyl-10-hydroxycamptothecin (SN38) combats cancer by inhibiting topoisomerase I. SN38 is one of the most active compounds among camptothecin derivatives. In addition, SN38 is also a theranostic reagent due to its intrinsic fluorescence. However, the poor water solubility, high systemic toxicity and limited action against drug resistance and metastasis of tumor cells of SN38 indicates that there is great space for the structural modification of SN38. From the perspective of chemical modification, this paper summarizes the progress of SN38 in improving solubility, increasing activity, reducing toxicity and possessing multifunction and analyzes the strategies of structure modification to provide a reference for drug development based on SN38.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements

“…Ethers, esters, carbamates, and carbonates have been substituted at C-10, providing various stimuli-responsive, tumor-targeted, synergistic, soluble, and theranostic delivery systems, with multifunctionality being ideal. 48,63,85 For instance, the folate-receptor-targeted and cathepsin B-sensitive FA-GFLG-SN38 (20, Figure 1) integrates enzymatic release, imaging, and targeting.…”

“…To overcome such limitations, substitution at C-10 and 20-OH is favored to enhance pharmacokinetic properties. Ethers, esters, carbamates, and carbonates have been substituted at C-10, providing various stimuli-responsive, tumor-targeted, synergistic, soluble, and theranostic delivery systems, with multifunctionality being ideal. ,, For instance, the folate-receptor-targeted and cathepsin B-sensitive FA-GFLG-SN38 ( 20 , Figure ) integrates enzymatic release, imaging, and targeting. Inactive 20 binds folate receptors on cancer cells, undergoing receptor-mediated endocytosis.…”

Development of a Targeted SN-38-Conjugate for the Treatment of Glioblastoma

“…7-Ethyl-10-hydroxycamptothecin, also known as SN-38, is an active metabolite of irinotecan, which has been reported to demonstrate 100–1000 times greater potency compared to irinotecan and displays potent inhibitory effects against DNA topoisomerase I. , SN-38 is an effective cytotoxic agent against primary and recurrent glioma cells. , However, it is lipophilic, highly toxic when administered intravenously, and unstable in the physiological environment, which limits its clinical application . Therefore, a peptide drug conjugate is ideal for improving SN-38’s low circulation half-life, solubility, and cytotoxicity profile.…”

Self-amplifying ROS-sensitive SN38 Dimeric Prodrug nanoparticles for Combined Chemotherapy and Ferroptosis in Cancer Treatment

“…Chemotherapy remains a cornerstone in tumor treatment strategies, and Camptothecin (CPT) has risen to prominence for its proficiency in inhibiting DNA damage through topoisomerase 1 [1]. Among its derivatives, 7-Ethyl-10-hydroxycamptothecin (SN38) stands out, mirroring CPT's mechanism and earning recognition as one of the most potent antitumor agents within this family [2]. SN38 has been reported to be 100-1000 times more effective against cancer in vitro than irinotecan (CPT-11) [3].…”